Total Synthesis of Anticancer Natural Products Using Oxidative Dearomatization

氧化脱芳构全合成抗癌天然产物

• 批准号: 9171740
• 负责人: Yu Yuan
• 金额: $ 43.62万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171740
• 关键词: Academic Research Enhancement Awards; Alkaloids; Ally; Antineoplastic Agents; Basic Science; Biological; Biology; Cancer Patient; Carbon; Cause of Death; Cells; Cephalotaxus; Cessation of life; Chemicals; Complex; Data; Development; Dose; Drug Industry; Economic Burden; Electron Transport; Electrons; Elements; Exhibits; Family; Intercept; Investigation; Laboratories; Longevity; Lymphoma; Malignant Neoplasms; Medical; Methodology; Methods; Mus; Natural Products; Navelbine ditartrate; Nerve Growth Factors; Norditerpenoids; Octanes; Organic Synthesis; Outcome; Oxidants; Paclitaxel; Patients; Phenols; Positioning Attribute; Protocols documentation; Radiation therapy; Reaction; Reagent; Regimen; Reporting; Research; Science; Scientist; Skeleton; Societies; Solid Neoplasm; Structure; Structure-Activity Relationship; System; Testing; Therapeutic Agents; United States; United States Food and Drug Administration; Up-Regulation; Vasodilation; alkaloid skeleton; analog; anticancer activity; base; chemotherapy; cycloaddition; cytotoxicity; diene; experience; improved; member; neoplastic cell; novel; novel therapeutics; operation; outcome forecast; oxidation; scaffold; skills; stereochemistry

PROJECT SUMMARY Cancer is the second leading cause of deaths in the United States and it has become a serious economic burden to society. Among the most successful treatments, natural product inspired chemotherapies such as Paclitaxel, Navelbine and Eribulin have significantly extended the life span of millions of cancer patients. It has been reported that more than 75% of the new chemical entities submitted to the Food and Drug Administration as anticancer agents between 1940 and 2010 have natural product origins. We propose to develop a novel oxidative dearomatization methodology to access the core structures of biologically active natural products and investigate its application to the total synthesis of daphmanidin A, an alkaloid showing significant cytotoxicity against murine lymphoma cells. Because some subtypes of lymphoma do not form solid tumors, their treatments commonly involve intense radiotherapy and chemotherapy. To improve the prognosis of patients who show low tolerance to current high dose regimens, new therapeutic agents with better efficacy are urgently needed. Given the cytotoxicity profiles of Daphniphyllum alkaloids, it is important to study the biology of daphmanidin A and explore its potential to become a therapeutic agent. Our preliminary data have shown that an enantioselective Michael addition / oxidative dearomatization cascade can be achieved by a one-pot operation, and the desired products are obtained with excellent stereoselectivity and yields, highlighting the remarkable efficiency of our strategy for the synthesis of these natural products. When para substituted phenols are subjected to the dearomatization, the core structures of Cephalotaxus norditerpenes are conveniently produced. When ortho substituted phenols are intercepted during the dearomatization, the spiro intermediates can serve as dienes in the subsequent [4+2] cycloaddition, resulting in the daphmanidin A type alkaloid skeletons. In the proposed research we will 1) identify the suitable single electron transfer reagent and base to enable the dearomatization for sensitive substrates under homogenous conditions; 2) study the regioselectivity for asymmetrically substituted aromatics; 3) examine the conditions to intercept spiro diene in the dearomatization; 4) elucidate the stereochemistry determining elements that control the chirality of the quaternary carbon center, and 5) apply the novel methodology to the synthesis of daphmanidin A and its pharmaceutically relevant analogues.

项目摘要 癌症是美国死亡的第二大原因，它已成为严重 社会的经济负担。在最成功的治疗中，天然产品受到启发 诸如紫杉醇，肚脐和eribulin之类的化学疗法显着延长了 数百万癌症患者。据报道，超过75％的新化学实体 在1940年至2010年之间，以抗癌代理的身份提交给食品和药物管理局 天然产品起源。我们建议开发一种新型的氧化型亲爱的方法来访问 生物活性天然产物的核心结构，并调查其在总计中的应用 达普胰素A的合成，一种生物碱，表现出对鼠淋巴瘤细胞的明显细胞毒性。 因为某些淋巴瘤的某些亚型不会形成实体瘤，所以它们的治疗通常涉及 强烈的放疗和化学疗法。提高表现低耐受性的患者的预后 对于当前的高剂量方案，迫切需要新的具有更好功效的治疗剂。给出 水diphyllum生物碱的细胞毒性谱，研究aphmanidin a的生物学很重要 并探索其成为治疗剂的潜力。 我们的初步数据表明，对映选择性的迈克尔添加 /氧化oratomatization 可以通过一锅操作来实现级联 立体选择性和产量，强调了我们策略合成的显着效率 这些天然产品。当para取代的苯酚受到珍贵的状态化时，核心 头甲烯烯的结构很方便地产生。当Ortho取代苯酚 在亲爱的疗法期间被拦截，螺旋中间体可以用作Dienes 随后的[4+2]环加成，导致了达夫甘丁A型生物碱骨骼。在提议中 研究我们将1）确定合适的单电子转移试剂和碱基以实现 在均匀条件下敏感底物的亲爱的； 2）研究的区域选择性 非对称取代的芳香剂； 3）检查拦截螺旋二烯的条件 亲爱的疗法； 4）阐明立体化学确定控制手性的元素 第四纪碳中心和5）将新方法应用于达夫曼类素A及其的合成 药品相关类似物。